Understanding of intentionality in children with Williams syndrome and Down syndrome, The

2012 Summer.Includes bibliographical references.This dissertation examined the development of the understanding of intentionality in two different neurogenetic disorders, Williams syndrome (WS) and Down syndrome (DS). The study of intentionality focuses on how children come to understand the intentions of others. Meltzoff's (1995) behavioral reenactment paradigm is a nonverbal procedure wherein a child is presented with a series of objects. Prior to each presentation, the examiner either performs a successful action (e.g. the target action) or an unsuccessful action (e.g. the failed intentional action). A child's understanding of intentionality is assessed by their ability to interpret the experimenter's intention during failed attempt trials, and their subsequent completion of the task. This examination of intentionality was divided into two studies. Study 1 was designed to test Tager-Flusberg and Sullivan's (2000) hypothesis that there is a dissociation between social-perceptual abilities and social-cognitive abilities in individuals with Williams syndrome. In order to explore this dissociation, the behavioral reenactment procedure was administered with and without experimenter affective cues. Participants were 25 children with a confirmed diagnosis of WS. There were two groups of WS, one that received affective cues (N=13) and one that did not (N=12). Also, children with WS in the no affect group were compared to 12 mental-age matched children with developmental disabilities. The findings of this study indicates that the understanding of intentionality improves with developmental status in children with WS. Also, this study indicates that there may be a dissociation between social-perceptual and social-cognitive skills in this population during early social-emotional development. Specifically, it seems that the presence of emotional cues during intersubjective tasks leads to an emotional response instead of a response based on social cognition. Study 2 was motivated by past research suggesting that children with DS demonstrate deficits in some aspects of social cognition, even though many children with DS have strengths in other aspects of social-emotional functioning. Therefore, it is likely that the understanding of intentionality in children with Down syndrome may be influenced by other foundational cognitive abilities (i.e. joint attention and affect sharing in early childhood and executive functioning in middle childhood). Participants were 40 children with a confirmed diagnosis of Down syndrome, 16 young children with DS and 24 older children with DS. In addition, the 16 young children with DS were compared to 16 mental-age matched children with other developmental disabilities. The results of this study suggests that the understanding of intentionality improves with developmental status for young children with DS. This study also suggest that difficulties in joint attention and EF lead children with DS to miss the target relevant information during the behavioral reenactment procedure leading them to perform more "other actions". This dissertation is the first study to examine the development of intentionality in WS and DS. From these studies, it may be possible to begin to characterize how the understanding of intentionality develops in children with WS and DS. Characterizing social cognition in WS and DS will help to identify areas for targeted intervention to prevent the possible cascading effects of difficulties in social cognition on other aspects of development

Eye Tracking as a Measure of Receptive Vocabulary in Children with Autism Spectrum Disorders

This study examined the utility of eye tracking research technology to measure speech comprehension in 14 young boys with autism spectrum disorders (ASD) and 15 developmentally matched boys with typical development. Using eye tracking research technology, children were tested on individualized sets of known and unknown words, identified based on their performance on the Peabody Picture Vocabulary Test. Children in both groups spent a significantly longer amount of time looking at the target picture when previous testing indicated the word was known (known condition). Children with ASD spent similar amounts of time looking at the target and non-target pictures when previous testing indicated the word was unknown (unknown condition). However, children with typical development looked longer at the target pictures in the unknown condition as well, potentially suggesting emergent vocabulary knowledge

The Role of Maternal Gesture Use in Speech Use by Children with Fragile X Syndrome

Purpose--The purpose of this study was to investigate how maternal gesture relates to speech production by children with fragile X syndrome (FXS). Method--Participants were 27 young children with FXS (23 boys, 4 girls) and their mothers. Videotaped home observations were conducted between the ages of 25 and 37 months (toddler period), and again between the ages of 60 and 71 months (child period). The videos were later coded for types of maternal utterances and maternal gestures that preceded child speech productions. Children were also assessed with the Mullen Scales of Early Learning at both ages Results--Maternal gesture use in the toddler period was positively related to expressive language scores at both age periods, and was related to receptive language scores in the child period. Maternal proximal pointing, in comparison to other gestures, evoked more speech responses from children during the mother-child interactions particularly when combined with wh-questions. Conclusion-- This study adds to the growing body of research on the importance of contextual variables, such as maternal gestures, in child language development. Parental gesture use may be an easily added ingredient to parent-focused early language intervention programs

HPA axis function predicts development of working memory in boys with FXS

The present study examines verbal working memory over time in boys with fragile X syndrome (FXS) compared to nonverbal mental-age (NVMA) matched, typically developing (TD) boys. Concomitantly, the relationship between cortisol—a physiological marker for stress—and verbal working memory performance over time is examined to understand the role of physiological mechanisms in cognitive development in FXS. Participants were assessed between one and three times over a 2-year time frame using two verbal working memory tests that differ in complexity: memory for words and auditory working memory with salivary cortisol collected at the beginning and end of each assessment. Multilevel modeling results indicate specific deficits over time on the memory for words task in boys with FXS compared to TD controls that is exacerbated by elevated baseline cortisol. Similar increasing rates of growth over time were observed for boys with FXS and TD controls on the more complex auditory working memory task, but only boys with FXS displayed an association of increased baseline cortisol and lower performance. This study highlights the benefit of investigations of how dynamic biological and cognitive factors interact and influence cognitive development over time

Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society

Best practices for constructing, preparing, and evaluating protein-ligand binding affinity benchmarks

Free energy calculations are rapidly becoming indispensable in structure-enabled drug discovery programs. As new methods, force fields, and implementations are developed, assessing their expected accuracy on real-world systems (benchmarking) becomes critical to provide users with an assessment of the accuracy expected when these methods are applied within their domain of applicability, and developers with a way to assess the expected impact of new methodologies. These assessments require construction of a benchmark - a set of well-prepared, high quality systems with corresponding experimental measurements designed to ensure the resulting calculations provide a realistic assessment of expected performance when these methods are deployed within their domains of applicability. To date, the community has not yet adopted a common standardized benchmark, and existing benchmark reports suffer from a myriad of issues, including poor data quality, limited statistical power, and statistically deficient analyses, all of which can conspire to produce benchmarks that are poorly predictive of real-world performance. Here, we address these issues by presenting guidelines for (1) curating experimental data to develop meaningful benchmark sets, (2) preparing benchmark inputs according to best practices to facilitate widespread adoption, and (3) analysis of the resulting predictions to enable statistically meaningful comparisons among methods and force fields

Proposal for a method to estimate nutrient shock effects in bacteria

Plating methods are still the golden standard in microbiology; however, some studies have shown that these techniques can underestimate the microbial concentrations and diversity. A nutrient shock is one of the mechanisms proposed to explain this phenomenon. In this study, a tentative method to assess nutrient shock effects was tested. Findings To estimate the extent of nutrient shock effects, two strains isolated from tap water (Sphingomonas capsulata and Methylobacterium sp.) and two culture collection strains (E. coli CECT 434 and Pseudomonas fluorescens ATCC 13525) were exposed both to low and high nutrient conditions for different times and then placed in low nutrient medium (R2A) and rich nutrient medium (TSA). The average improvement (A.I.) of recovery between R2A and TSA for the different times was calculated to more simply assess the difference obtained in culturability between each medium. As expected, A.I. was higher when cells were plated after the exposition to water than when they were recovered from high-nutrient medium showing the existence of a nutrient shock for the diverse bacteria used. S. capsulata was the species most affected by this phenomenon. This work provides a method to consistently determine the extent of nutrient shock effects on different microorganisms and hence quantify the ability of each species to deal with sudden increases in substrate concentration. <br/

Towards W b bbar + j at NLO with an automatized approach to one-loop computations

We present results for the O(alpha_s) virtual corrections to q g -> W b bbar q' obtained with a new automatized approach to the evaluation of one-loop amplitudes in terms of Feynman diagrams. Together with the O(alpha_s) corrections to q q' -> W b bbar g, which can be obtained from our results by crossing symmetry, this represents the bulk of the next-to-leading order virtual QCD corrections to W b bbar + j and W b + j hadronic production, calculated in a fixed-flavor scheme with four light flavors. Furthermore, these corrections represent a well defined and independent subset of the 1-loop amplitudes needed for the NNLO calculation of W b bbar. Our approach was tested against several existing results for NLO amplitudes including selected O(alpha_s) one-loop corrections to W + 3 j hadronic production. We discuss the efficiency of our method both with respect to evaluation time and numerical stability.Comment: 14 pages, 3 figure

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1